Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods

ABSTRACT

Biocompatible intraocular implants include a tyrosine kinase inhibitor and a biodegradable polymer that is effective to facilitate release of the tyrosine kinase inhibitor into an eye for an extended period of time. The therapeutic agents of the implants may be associated with a biodegradable polymer matrix, such as a matrix that is substantially free of a polyvinyl alcohol. The implants may be placed in an eye to treat or reduce the occurrence of one or more ocular conditions.

BACKGROUND

The present invention generally relates to devices and methods to treatan eye of a patient, and more specifically to intraocular implants thatprovide extended release of a therapeutic agent to an eye in which theimplant is placed, and to methods of making and using such implants, forexample, to treat or reduce one or more symptoms of an ocular condition.

Delivery of drugs to the retina, vitreous and uveal tract is typicallyachieved by high systemic dosing, intra-ocular injections or otherheroic measures. Penetration of systemically administered drugs into theretina is severely restricted by the blood-retinal barriers (BRB) formost compounds. Although intraocular injection, such as intravitrealinjections, resolves some constraints posed by the BRB and significantlyreduces the risk of systemic toxicity, intraocular injection techniquesmay result in retinal detachment, physical damage to the lens, exogenousendophthalmitis, and also may result in high pulsed concentrations ofdrug at the lens and other intraocular tissues.

Compounds are eliminated from the vitreous by diffusion to theretro-zonular space with clearance via the aqueous humor or bytrans-retinal elimination. Most compounds utilize the former pathwaywhile lipophilic compounds and those with trans-retinal transportmechanisms will utilize the latter. Unfortunately, compounds that areeliminated across the retina have extremely short half-lives. Hence, forthese compounds it is difficult to maintain therapeutic concentrationsby direct intraocular injection, and therefore, frequent injection isoften required.

Additionally, the rapid elimination of retinaly cleared compounds makesformulation of controlled delivery systems challenging. For example,tyrosine kinase inhibitors (TKIs) may possess extremely shortintraocular half-lives, and thus, may pose a challenge to theformulation of controlled delivery systems. The inventors are unaware ofany small molecule TKIs given by intraocular administration, let alone,intraocular implants containing TKIs.

U.S. Pat. No. 6,713,081 discloses ocular implant devices made frompolyvinyl alcohol and used for the delivery of a therapeutic agent to aneye in a controlled and sustained manner. The implants may be placedsubconjunctivally or intravitreally in an eye.

Biocompatible implants for placement in the eye have also been disclosedin a number of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224;4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072;5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493.

It would be advantageous to provide eye implantable drug deliverysystems, such as intraocular implants, and methods of using suchsystems, that are capable of releasing a therapeutic agent at asustained or controlled rate for extended periods of time and in amountswith few or no negative side effects.

SUMMARY

The present invention provides new drug delivery systems, and methods ofmaking and using such systems, for extended or sustained drug releaseinto an eye, for example, to achieve one or more desired therapeuticeffects. The drug delivery systems are in the form of implants orimplant elements that may be placed in an eye. The present systems andmethods advantageously provide for extended release times of one or moretherapeutic agents. Thus, the patient in whose eye the implant has beenplaced receives a therapeutic amount of an agent for a long or extendedtime period without requiring additional administrations of the agent.For example, the patient has a substantially consistent level oftherapeutically active agent available for consistent treatment of theeye over a relatively long period of time, for example, on the order ofat least about one week, such as between about one and about six monthsor even for more than one year after receiving an implant. Such extendedrelease times facilitate obtaining successful treatment results. Theimplants allow for prolonged delivery of a therapeutic agent whilereducing invasive procedures and reducing high transient concentrationsassociated with pulsed dosing.

Intraocular implants in accordance with the disclosure herein comprise atherapeutic component and a drug release sustaining component associatedwith the therapeutic component. The implants may be solid, semisolid, orviscoelastic. In accordance with the present invention, the therapeuticcomponent comprises, consists essentially of, or consists of, a tyrosinekinase inhibitor (TKI), for example, an agent or compound that inhibitsor reduces the activity of tyrosine kinase. The TKI may also beunderstood to be a small molecule TKI. The drug release sustainingcomponent is associated with the therapeutic component to sustainrelease of an amount of the TKI into an eye in which the implant isplaced. TKIs may be released from the implant by diffusion, erosion,dissolution or osmosis. The drug release sustaining component maycomprise one or more biodegradable polymers or one or morenon-biodegradable polymers. Examples of biodegradalbe polymers of thepresent implants may include poly-lactide-co-glycolide (PLGA and PLA),polyesters, poly(ortho ester), poly(phosphazine), poly(phosphate ester),polycaprolactone, natural polymers such as gelatin or collagen, orpolymeric blends. The amount of the TKI is released into the eye for aperiod of time greater than about one week after the implant is placedin the eye and is effective in reducing or treating an ocular condition.

In one embodiment, the intraocular implants comprise a TKI and abiodegradable polymer matrix. The TKI is associated with a biodegradablepolymer matrix that degrades at a rate effective to sustain release ofan amount of the TKI from the implant effective to treat an ocularcondition. The intraocular implant is biodegradable or bioerodible andprovides a sustained release of the TKI in an eye for extended periodsof time, such as for more than one week, for example for about one monthor more and up to about six months or more. The implants may beconfigured to provide release of the therapeutic agent in substantiallyone direction, or the implants may provide release of the therapeuticagent from all surfaces of the implant.

The biodegradable polymer matrix of the foregoing implants may be amixture of biodegradable polymers or the matrix may comprise a singletype of biodegradable polymer. For example, the matrix may comprise apolymer selected from the group consisting of polylactides,poly(lactide-co-glycolides), polycaprolactones, and combinationsthereof.

In another embodiment, intraocular implants comprise a therapeuticcomponent that comprises a TKI, and a polymeric outer layer covering thetherapeutic component. The polymeric outer layer includes one or moreorifices or openings or holes that are effective to allow a liquid topass into the implant, and to allow the TKI to pass out of the implant.The therapeutic component is provided in a core or interior portion ofthe implant, and the polymeric outer layer covers or coats the core. Thepolymeric outer layer may include one or more non-biodegradableportions. The implant can provide an extended release of the TKI formore than about two months, and for more than about one year, and evenfor more than about five or about ten years. One example of such apolymeric outer layer covering is disclosed in U.S. Pat. No. 6,331,313.

Advantageously, the present implants provide a sustained or controlleddelivery of therapeutic agents at a maintained level despite the rapidelimination of the TKIs from the eye. For example, the present implantsare capable of delivering therapeutic amounts of a TKI for a period ofat least about 30 days to about a year despite the short intraocularhalf-lives associated with TKIs. Plasma TKI levels obtained afterimplantation are extremely low, thereby reducing issues or risks ofsystemic toxicity. The controlled delivery of the TKIs from the presentimplants permits the TKIs to be administered into an eye with reducedtoxicity or detioration of the blood-aqueous and blood-retinal barriers,which may be associated with intraocular injection of liquidformulations containing TKIs.

A method of making the present implants involves combining or mixing theTKI with a biodegradable polymer or polymers. The mixture may then beextruded or compressed to form a single composition. The singlecomposition may then be processed to form individual implants suitablefor placement in an eye of a patient.

Another method of making the present implants involves providing apolymeric coating around a core portion containing a TKI, wherein thepolymeric coating has one or more holes.

The implants may be placed in an ocular region to treat a variety ofocular conditions, such as treating, preventing, or reducing at leastone symptom associated with non-exudative age related maculardegeneration, exudative age related macular degeneration, choroidalneovascularization, acute macular neuroretinopathy, cystoid macularedema, diabetic macular edema, Behcet's disease, diabetic retinopathy,retinal arterial occlusive disease, central retinal vein occlusion,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser treatment, conditions caused by photodynamic therapy,photocoagulation, radiation retinopathy, epiretinal membranes,proliferative diabetic retinopathy, branch retinal vein occlusion,anterior ischemic optic neuropathy, non-retinopathy diabetic retinaldysfunction, retinitis pigmentosa, ocular tumors, ocular neoplasms, andthe like.

Kits in accordance with the present invention may comprise one or moreof the present implants, and instructions for using the implants. Forexample, the instructions may explain how to administer the implants toa patient, and types of conditions that may be treated with theimplants.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent. In addition, any feature orcombination of features may be specifically excluded from any embodimentof the present invention.

Additional aspects and advantages of the present invention are set forthin the following description and claims, particularly when considered inconjunction with the accompanying drawings.

DRAWINGS

FIG. 1 is a graph showing the vitreous humor concentration of two TKIsas a function of time.

FIG. 2 is a graph similar to FIG. 1 for two different TKIs.

FIG. 3 is a graph of the cumulative release profile for AGN 200954 as afunction of time.

FIG. 4 is a graph of the cumulative release profile for AGN 202314 as afunction of time.

FIG. 5 is a graph similar to FIG. 4 for different formulations of AGN202314.

FIG. 6 is a graph of the TTL release for AGN 201634 as a function oftime.

FIG. 7 is a graph similar to FIG. 6 with implants containing 30% AGN201634.

FIG. 8 is a graph similar to FIG. 6 for AGN 201634 in differentsolutions.

FIG. 9 is a graph of the percent of TKI released as a function of timein different a Tween 80/saline solution.

FIG. 10 is a graph similar to FIG. 9 except in a phosphate buffersolution.

FIG. 11 is a graph of the cumulative release profile for TKI AGN 201634of Formulation 1 in saline and PBS.

FIG. 12 is a graph of the cumulative release profile for TKI AGN 201634release of Formulation 3 in media of a pH of 6.0 (with 0.1% CTAB), 7.4(PBS) or 8.5 (with 0.5% SDS).

FIG. 13 is a graph of the cumulative release profile for TKI AGN 201634release of Formulation 4 in media of a pH of 6.0 (with 0.1% CTAB), 7.4(PBS) or 8.5 (with 0.5% SDS).

FIG. 14 is an illustration of a biodegradable implant comprising adrug-releasing active layer and a barrier layer.

FIG. 15 is a graph of the cumulative release profile for aTKI-containing implant and Dexamethasone-containing implants, in whichthe biodegradable polymer is polycaprolactone.

DESCRIPTION

As described herein, controlled and sustained administration of atherapeutic agent through the use of one or more intraocular implantsmay improve treatment of undesirable ocular conditions. The implantscomprise a pharmaceutically acceptable polymeric composition and areformulated to release one or more pharmaceutically active agents, suchas tyrosine kinase inhibitors (TKIs), over an extended period of time.The implants are effective to provide a therapeutically effective dosageof the agent or agents directly to a region of the eye to treat,prevent, and/or reduce one or more symptoms of one or more undesirableocular conditions. Thus, with a single administration, therapeuticagents will be made available at the site where they are needed and willbe maintained for an extended period of time, rather than subjecting thepatient to repeated injections or, in the case of self-administereddrops, ineffective treatment with only limited bursts of exposure to theactive agent or agents.

An intraocular implant in accordance with the disclosure hereincomprises a therapeutic component and a drug release sustainingcomponent associated with the therapeutic component. In accordance withthe present invention, the therapeutic component comprises, consistsessentially of, or consists of, a TKI. The drug release sustainingcomponent is associated with the therapeutic component to sustainrelease of an effective amount of the therapeutic component into an eyein which the implant is placed. The amount of the therapeutic componentis released into the eye for a period of time greater than about oneweek after the implant is placed in the eye, and is effective intreating and/or reducing at least one symptom of one or more ocularconditions, such as conditions wherein migration or proliferation ofretinal pigment epithelium or glial cells causes or contributes to thecause of the condition. Some examples of ocular conditions that may betreated with the implants of the present invention include, withoutlimitation, non-exudative age related macular degeneration, exudativeage related macular degeneration, choroidal neovascularization, acutemacular neuroretinopathy, cystoid macular edema, diabetic macular edema,Behcet's disease, diabetic retinopathy, retinopathy of prematurity,retinal arterial occlusive disease, central retinal vein occlusion,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser treatment, conditions caused by photodynamic therapy,photocoagulation, radiation retinopathy, epiretinal membranes,proliferative diabetic retinopathy, branch retinal vein occlusion,anterior ischemic optic neuropathy, non-retinopathy diabetic retinaldysfunction, retinitis pigmentosa, ocular tumors, ocular neoplasms, andthe like.

Definitions

For the purposes of this description, we use the following terms asdefined in this section, unless the context of the word indicates adifferent meaning.

As used herein, an “intraocular implant” refers to a device or elementthat is structured, sized, or otherwise configured to be placed in aneye. Intraocular implants are generally biocompatible with physiologicalconditions of an eye and do not cause adverse side effects. Intraocularimplants may be placed in an eye without disrupting vision of the eye.

As used herein, a “therapeutic component” refers to a portion of anintraocular implant comprising one or more therapeutic agents orsubstances used to treat a medical condition of the eye. The therapeuticcomponent may be a discrete region of an intraocular implant, or it maybe homogenously distributed throughout the implant. The therapeuticagents of the therapeutic component are typically ophthalmicallyacceptable, and are provided in a form that does not cause adversereactions when the implant is placed in an eye.

As used herein, a “drug release sustaining component” refers to aportion of the intraocular implant that is effective to provide asustained release of the therapeutic agents of the implant. A drugrelease sustaining component may be a biodegradable polymer matrix, orit may be a coating covering a core region of the implant that comprisesa therapeutic component.

As used herein, “associated with” means mixed with, dispersed within,coupled to, covering, or surrounding.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of areas ofthe eyeball in an ocular region include the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

As used herein, an “ocular condition” is a disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein erosion of the polymer or polymers overtimeoccurs concurrent with or subsequent to release of the therapeuticagent. Specifically, hydrogels such as methylcellulose which act torelease drug through polymer swelling are specifically excluded from theterm “biodegradable polymer”. The terms “biodegradable” and“bioerodible” are equivalent and are used interchangeably herein. Abiodegradable polymer may be a homopolymer, a copolymer, or a polymercomprising more than two different polymeric units.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of agent needed to treat an ocular condition, orreduce or prevent ocular injury or damage without causing significantnegative or adverse side effects to the eye or a region of the eye.

Intraocular implants have been developed which can release drug loadsover various' time periods. These implants, which when inserted into aneye, such as the vitreous of an eye, provide therapeutic levels of aTKI, for extended periods of time (e.g., for about 1 week or more). Thedisclosed implants are effective in treating ocular conditions, such asnon-exudative age related macular degeneration, exudative age relatedmacular degeneration, choroidal neovascularization, acute macularneuroretinopathy, cystoid macular edema, diabetic macular edema,Behcet's disease, diabetic retinopathy, retinal arterial occlusivedisease, central retinal vein occlusion, uveitic retinal disease,retinal detachment, trauma, conditions caused by laser treatment,conditions caused by photodynamic therapy, photocoagulation, radiationretinopathy, epiretinal membranes, proliferative diabetic retinopathy,branch retinal vein occlusion, anterior ischemic optic neuropathy,non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa,ocular tumors, ocular neoplasms, and the like.

In one embodiment of the present invention, an intraocular implantcomprises a biodegradable polymer matrix. The biodegradable polymermatrix is one type of a drug release sustaining component. Thebiodegradable polymer matrix is effective in forming a biodegradableintraocular implant. The biodegradable intraocular implant comprises aTKI associated with the biodegradable polymer matrix. The matrixdegrades at a rate effective to sustain release of an amount of the TKIfor a time greater than about one week from the time in which theimplant is placed in ocular region or ocular site, such as the vitreousof an eye.

The TKI of the implant is typically an agent that inhibits or reducesthe activity of a tyrosine kinase. The TKI may inhibit tyrosine kinaseactivity by directly acting on a tyrosine kinase molecule, or it maycooperate with one or more other factors or agents to achieve thedesired inhibition. Examples of TKIs useful in the present implants aredescribed in U.S. patent application Ser. No. 10/256,879 (U.S. Pub. No.20030199478) and Ser. No. 10/259,703 (U.S. Pub. No. 20030225152).

In short, a TKI of the present implants include organic moleculescapable of modulating, regulating and/or inhibiting tyrosine kinasesignal transduction. Some compounds useful in the present implants arerepresented by the following formula

wherein R¹ is selected from the group consisting of halogen, NO₂, CN, C₁to C₄ alkyl and aryl, e.g. phenyl; R² is selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, COCH₃, CH₂CH₂OH, CH₂CH₂CH₂OH andphenyl; R is selected from the group consisting of D, halogen, C₁ to C₈alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, SR², (CR⁷R⁸)_(c)C(O)OR², C(O)N(R²)₂,(CR⁷, R⁸)_(c)OR², HNC(O)R², HN—C(O)OR², (CR⁷R⁸)_(c)N(R²)₂, SO₂(CR⁷R⁸)_(c)N(R²)₂, OP(O)(OR²)₂, OC(O)OR², OCH₂O, HN—CH═CH,—N(COR²)CH₂CH₂, HC═N—NH, N═CH—S, O(CR⁷R⁸)_(d)—R⁶ and (CR⁷R⁸)_(c)—R⁶,—NR₂(CR⁷R⁸)_(d)R⁶ wherein R⁶ is selected from the group consisting ofhalogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methylisonipecotate, N-(2-methoxyethyl)-N-methylamyl,1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl,piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl,thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethylyl, 3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N-BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran,ethanolamine and alkyl-substituted derivatives thereof and wherein whenc is 1 said CH₂ may be

and CH₂CH₂CH₂; provided said alkyl or phenyl radicals may be substitutedwith one or two halo, hydroxy or lower alkyl amino radicals wherein R⁷and R⁸ may be selected from the group consisting of H, F and C₁-C₄ alkylor CR⁷R⁸ may represent a carbocyclic ring of from 3 to 6 carbons,preferably R⁷ and R⁸ are H or CH₃;

b is 0 or an integer of from 1 to 3;

a is 0 or an integer of from 1 to 5, preferably 1 to 3;

c is 0 or an integer of from 1 to 4,

d is an integer of from 2 to 5;

the wavy line represents a E or Z bond and pharmaceutically acceptablesalts thereof.

In certain implants, the TKI is a compound having the foregoing formula,wherein R¹ is selected from the group consisting of H, i.e. b is 0; CH₃,F, Cl and phenyl.

Preferably, R is selected from the group consisting of CH₃, CH₂CH₃,OCH₃, OH, t-butyl, F, CN, C(O)NH₂, HN C(O)CH₃, CH₂C(O)OH, SO₂NH₂,C(O)OH, OCF₂H, isopropyl, C₂H₅OH, C(O)OCH₃, CH₂OH, NH—CH═CH, HC═N—N—H,N═CH—S, O(CR⁷R⁸)_(d)R⁶, (CR⁷R⁸)_(c)R⁶ and —NR²(CR⁷R⁸)_(d)R⁶, wherein R⁶is selected from the group consisting of 3-fluoropyrrolidinyl,3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate,N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl,morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl,N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl,1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethyl)-1,3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N-BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl,4-aminomethyltetrahydropyranyl, ethanolamine and alkyl-substitutedderivatives thereof, e.g. R⁶ is morpholinyl or CH₂N(CH₃)₂.

More preferably, R is selected from the group consisting of m-ethyl,p-methoxy, p-hydroxy, m-hydroxy, p-cyano, m-C(O)NH₂, p-HNC(O)CH₃,p-CH₂C(O)OH, p-SO₂NH₂, p-CH₂OH, m-methoxy, p-CH₂CH₂OH, HNCH═CH, HC═N—NH,p-morpholinyl, N═CH—S, p-OCHF₂, p-COOH, p-CH₃, p-OCH₃, m-F,m-CH₂N(C₂H₃)₂, (CR⁷R⁸)_(c)R⁶, O(CR⁷R⁸)_(d)R⁶ and NR²(CR⁷R⁸)_(d)R⁶.

It is noted that R may represent a condensed ring that is attached tothe above phenyl ring at two positions. For example, CH₂CH₂CH₂ may beattached at the 3 and 4 (or m and p) positions of the phenyl ring.

Still more preferably, R is selected from the group consisting offluoro, methyl, (CR⁷R⁸)_(c)R⁶, O(CR⁷R⁸)_(d)R⁶ and NR²(CR⁷R⁸)_(d)R⁶wherein R⁶ is selected from dimethylamino, diethylamino,3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 3-pyridinyl, 4-pyridinyl,pyrrolidinyl, morpholinyl, piperazinyl, heptamethyleneiminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyranyl,N,N-diisopropylethylenediaminyl and 4-aminomethyltetrahydropyran.

In particular, the compounds of the present implants may be selectedfrom the compounds of the tables below.

TABLE 1 Unsubstituted 4-Methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-in- dol-2-ones.

R Substitution 1. Example # R¹ 2 3 4 5 6 1 H H H H H H 2 H H Br H H H 3H H H Br H H 4 H Br H H H H 5 H H H Et H H 6 H H Et H H H 7 H H H OMe HH 8 H H H CO₂Et H H 9 H Et H H H H 10 H H F Me H H 11 H Me F H H H 12 HH H OH H H 13 H H Cl OH H H 14 H Me H F H H 15 H H OH H H H 16 H H OMe HOMe H 17 H H H tBu H H 18 H H H Me H H 19 H H Me H Me H 20 H H Me Me H H21 H H F OMe H H 22 H H CF₃ H H H 23 H H —CH₂CH₂CH₂— H H 24 H F H Cl H H25 H H H CF₃ H H 26 H F H Me OCO₂Et H 27 H F H Me OCO₂CH₂C(CH₃)₃ H 28 HF H Cl OH H 29 H H H CN H H 30 H H H CH₂CN H H 31 H H —CH═CH—NH— H H 32H H —NH—N═CH— H H 33 H H H CONH₂ H H 34 H H H NHCOCH₃ H H 35 H H CH₂CO₂HH H H 36 H H H Cl H H Unsubstituted, 4-methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-di- hydro-indol-2-ones.

R Substitution 2. Example # R¹ 2 3 4 5 6 37 H H CO₂H Cl H H 38 H H HSO₂NH₂ H H 39 H H H SO₂NHCOCH₃ H H 40 H H H N-morpholino H H 41 H H HOPh H H 42 H H OMe OMe H H 43 H H —S—CH═N— H H 44 H H OH CO₂H H H 45 H HCF₃ Cl H H 46 H H CF₃ H CF₃ H 47 H H CF₃ F H H 48 H H OH Me H H 49 H HOH OMe H H 50 H H H OCHF₂ H H 51 H H H OCF₃ H H 52 H H H iPr H H 53 H FH Me H H 54 H H Me Cl H H 55 H H CF₃ OMe H H 56 H H CF₃ Me H H 57 5′-ClH OMe H H H 58 4′-Me H H H H H 59 4′-Me H H OMe H H 60 4′-Me H OH H H H61 4′-Me H OMe H OMe H 62 4′-Me H H Me H H 63 4′-Me H Me H Me H 64 5′-ClH H OCHF₂ H H 65 5′-Cl H OH OMe H H 66 5′-Cl H H OCF₃ H H 67 5′-Cl H MeOH H H 68 5′-Cl H —OCH₂O— H H 69 5′-Cl H Me Me H H 70 5′-Cl H H iPr H H71 5′-Cl H OH Me H H 72 5′-Cl H H (CH₂)₂OH H H Unsubstituted, 4-methyl &5-Chloro 3-[(Substituted Phenylamino)-methylene]-1,3-dihydro-in-dol-2-ones.

R Substitution 3. Example # R¹ 2 3 4 5 6 73 5′-Cl H H OMe H H 74 5′-Cl HH H H H 75 5′-Cl H OMe H OMe H 76 5′-Cl H OH H H H 77 5′-Cl H H OH H H78 5′-Cl H Me H Me H 79 5′-Cl H H Me H H 80 H H —OCH₂O— H H 81 H H CO₂HOH H H 82 H H H OEt H H 83 H H —N(COMe)—CH₂—CH₂— H H 84 H H H OPO(OH)₂ HH 85 H H CO₂H CO₂H H H 86 H H H CO₂H H H 87 H H H (CH₂)₂OH H H 88 H H HCH₂OH H H 89 H H OMe CO₂CH₃ H H 90 4′-Me H —NH—N═CH— H H 91 4′-Me H FOMe H H 92 4′-Me H —S—CH═N— H H 93 4′-Me H OMe CO₂CH₃ H H 94 H H OMe H HH 95 4′-Me H Me Me H H 96 4′-Me H H OH H H 97 4′-Me H —CH═CH—NH— H H 984′-Me H H t-Bu H H 99 4′-Me H H CH₂OH H H 100 5′-Cl H H t-Bu H H 1015′-Cl H —S—CH═N— H H 102 5′-Cl H OMe OMe H H 103 5′-Cl H —NH—N═CH— H H104 5′-Cl OMe H Cl OMe H 105 5′-Cl H F OMe H H 106 5′-Cl H HN-morpholino H H 107 5′-Cl H H OEt H H 108 5′-Cl H CO₂H OH H HUnsubstituted, 4-methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-in- dol-2-ones.

R Substitution 4. Example # R¹ 2 3 4 5 6 109 5′-Cl H CH₂NEt₂ OH H H 1105′-Cl H —CH═CH—NH— H H 111 5′-Cl H H CH₂OH H H 112 5′-Cl H Me iPr H H113 4′-Me H H CH₂CH₂OH H H 114 5′-Cl H H NHCOMe H H 115 5′-Cl H HCH₂CO₂H H H 116 5′-Cl H H SO₂NH₂ H H 117 4′-Me H OH OMe H H 118 4′-Me HCO₂H OH H H 119 4′-Me H H OCHF₂ H H 120 4′-Me H H OCF₃ H H 121 4′-Me HCF₃ OMe H H 122 4′-Me H H OEt H H 123 4′-Me H H iPr H H 124 4′-Me H—O—CH₂—O— H H 125 4′-Me H OH Me H H 126 4′-Me H OMe OMe H H 127 4′-Me EtH H H H 128 4′-Me H H CN H H 129 4′-Me H H CONH₂ H H 130 4′-Me H HNHCOCH₃ H H 131 4′-Me H H CH₂CO₂H H H 132 4′-Me H Me OH H H 133 H H MeOH H H 134 H H OH NHCO₂Et H H 135 4′-Me F H OMe H H 136 H H H SMe H H137 4′-Me H H SMe H H 138 5′-Cl H H SMe H H 139 H H H —CH₂CH₂CH₂CO₂H H H140 4′-Me H H —CH₂CH₂CH₂CO₂H H H 141 H H —CH₂CH₂CO₂H H H H 142 4′-Me H—CH₂CH₂CO₂H H H H 143 5′-Cl H —CH₂CH₂CO₂H H H H 144 H H H —CH₂CH₂CO₂H HH 145 4′-Me H H —CH₂CH₂CO₂H H H 146 5′-Cl H H —CH₂CH₂CO₂H H HUnsubstituted, 4-methyl, 5-Chloro & 5-Fluoro 3-[(Substituted Phenyl-amino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 5. Example # R¹ 2 3 4 5 6 147 4′-Me H Et H H H 148 5′-ClH Et H H H 149 5′-Cl H H Et H H 150 5′-Cl H H —CH₂CH₂CH₂CO₂H H H 1514′-Me H H Et H H 152 5′-Cl H H —CN H H 155 4′-Me H OH CO₂H H H 156 H H HN(Me)₂ H H 157 H H H

H H 158 H H H

H H 159 H H H

H H 160 H H CH₂N(Et)₂ OH H H 161 4′-Me H CH₂N(Et)₂ OH H H 162 5′-F H—CH═CH—NH— H H 163 5′-F H —NH—N═CH— H H 164 5′-F H OH OMe H H 165 5′-F HH CH₂CH₂CO₂H H H 166 5′-F H H SO₂NH₂ H H 167 5′-F H H

H H 168 5′-F H H

H H 169 5′-F H H H H H 170 5′-F H H CONH₂ H H 171 5′-F H H SMe H H 1725′-F H F OMe H H 173 5′-F H —S—CH═N— H H 174 5′-F H H CH₂CO₂H H H 1755′-F H CH₂CH₂CO₂H H H H 176 5′-F H Et H H H Unsubstituted, 4-methyl,5-Chloro & 5-Fluoro 3-[(Substituted Phenylamino)-methylene]-1,3-di-hydro-indol-2-ones.

R Substitution 6. Example # R¹ 2 3 4 5 6 177 5′-F H OH H H H 178 5′-F HH CH₂OH H H 179 H H H

H H 180 H H H NH₂ H H 181 4′-Me H H NH₂ H H 182 H H CH(OH)CH₃ H H H 1834′-Me H CH(OH)CH₃ H H H 184 H H CH₂OH H H H 185 4′-Me H CH₂OH H H H 186H H NHCO₂t-Bu H H H 187 4′-Me H NHCO₂t-Bu H H H 188 H H H N(Et)₂ H H 1894′-Me H H N(Et)₂ H H 190 H H SO₂N(CH₂CH₂OH)₂ H H H 191 4′-Me HSO₂N(CH₂CH₂OH)₂ H H H 192 H H H SO₂NCH₂CH₂OH H H 193 H H SO₂NCH₂CH₂CH₂OHH H H 194 4′-Me H SO₂NCH₂CH₂CH₂OH H H H 195 H H CO₂H

H H 196 4′-Me H H

H H 197 4′-Me H H SO₂NCH₂CH₂OH H H 198 H H H OCH₂CH₂CH₂Cl H H 199 H H HOCH₂CH₂CH₂CH₂Cl H H 200 H H H OCH₂CH₂CH₂I H H 201 H H H OCH₂CH₂CH₂CH₂I HH 202 4′-Me D D D D D 203 H D D CO₂H D D 204 H D D NH₂ D D 205 4′-Me D DNH₂ D D Unsubstituted, 4-methyl, 5-Chloro & 5-Fluoro 3-[(SubstitutedPhenylamino)-methylene]-1,3-di- hydro-indol-2-ones.

R Substitution 7. Example # R¹ 2 3 4 5 6 206 H H H

H H 207 H H H OCH₂CH₂CH₂CH₂N(Et)₂ H H 208 H H H

H H 209 H H H

H H 210 4′-Me H NH₂ H H H 211 H H NH₂ H H H 212 H H NH₂ Me H H 213 4′-MeH NH₂ Me H H 214 H H H OCH₂CH₂CH₂N(Et)₂ H H 215 H H H

H H 216 H H H

H H 217 H H H

H H 218 H H H

H H 219 5′-F H H

H H 220 4′-Me H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 8. Example # R¹ 2 3 4 5 6 221 5′-F H H

H H 222 5′-F H H OMe H H 223 H D D D D D 224 H H H CH₂CO₂H H H 225 H H H

H H 226 H H H

H H 227 4′-Me H H

H H 228 6′-F H H

H H 229 6′-F H H

H H 230 6′-F H H

H H 231 4′-Me H H

H H 232 5′-Cl H H

H H 233 5′-F H H

H H 234 6′-F H H

H H 235 H H H

H H 236 5′-NO₂ H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 9. Example # R¹ 2 3 4 5 6 237 5′-CN H H

H H 238 4′-Me H H

H H 239 6′-F H H

H H 240 5′-F H H

H H 241 5′-Cl H H

H H 242 4′-Me H H

H H 243 6′-F H H

H H 244 5′-F H H

H H 245 5′-Cl H H

H H 246 4′-Me H H

H H 247 6′-F H H

H H 248 H H F

H H 249 4′-Me H F

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones.

Substitution 10. Example # R¹ 2 3 4 5 6 250 6′-F H F

H H 251 H H H

H H 252 4′-Me H H

H H 253 6′-F H H

H H 254 H H H

H H 255 4′-F H H

H H 256 4′-Me H H

H H 257 4′-F H H

H H 258 5′-F H H

H H 259 6′-F H H

H H 260 5′-Cl H H

H H 261 4′-F H H

H H 262 5′-Cl H H

H H 263 5′-F H H

H H 264 4′-Me H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 11. Example # R¹ 2 3 4 5 6 265 H H H

H H 266 6′-F H H

H H 267 4′-F H H

H H 268 6′-(3-Methoxyphenyl) H H

H H 269 6′-(3-Methoxyphenyl) H H

H H 270 4′-Me H H

H H 271 6′-F H H

H H 272 H H H

H H 273 4′-F H H

H H 274 5′-F H H

H H 275 5′-Cl H H

H H 276 6′-(3-Methoxyphenyl) H H

H H 277 6′-(3-Methoxyphenyl) H H

H H 278 4′-Me H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhanylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 12. Example # R¹ 2 3 4 5 6 279 6′-F H H

H H 280 H H H

H H 281 4′-F H H

H H 282 5′-F H H

H H 283 5′-Cl H H

H H 284 H H H

H H 285 5′-Cl H H

H H 286 4′-Me H H

H H 287 4′-F H H

H H 288 5′-F H H

H H 289 6′-F H H

H H 290 H H H

H H 291 5′-Cl H H

H H 292 4′-Me H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro,5-Nitro, 6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 13. Example # R¹ 2 3 4 5 6 293 4′-F H H

H H 294 5′-F H H

H H 295 6′-F H H

H H 296 4′-Me H H

H H 297 H H H

H H 298 6′-F H H

H H 299 5′-Cl H H

H H 300 5′-F H H

H H 301 4′-F H H

H H 302 H H H

H H 303 4′-Me H H

H H 304 6′-F H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Fluoro & 6-Fluoro3-[(Substituted Phenyl- amino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 14. Example # R¹ 2 3 4 5 6 305 H H H

H H 306 H H H

H H 307 5′-Cl H H

H H 308 4′-Me H H

H H 309 4′-F H H

H H 310 5′-F H H

H H 311 6′-F H H

H H 312 H H H

H H 313 5′-Cl H H

H H 314 4′-Me H H

H H 315 4′-F H H

H H 316 5′-F H H

H H 317 6′-F H H

H H Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Fluoro & 6-Fluoro3-[(Substituted Phenyl- amino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution 15. Example # R¹ 2 3 4 5 6 318 H H H

H H 319 5′-Cl H H

H H 320 4′-Me H H

H H 321 4′-F H H

H H 322 5′-F H H

H H 323 6′-F H H

H H

The present implants may also comprise a TKI or a combination of TKIsrepresented by the following formulas

Additional TKIs that may be used in the present implants include thosecompounds disclosed in Goel et al., “Tyrosine Kinase Inhibitors: AClinical Perspective”, Current Oncology Reports, 4:9-19 (2002); Haluskaet al., “Receptor tyrosine kinase inhibitors”, Current Opinion inInvestigational Drugs, 2(2):280-286 (2001); Hubbard et al., “Proteintyrosine kinase structure and function”, Annu. Rev. Biochem., 69:373-98(2000); Busse et al., “Tyrosine kinase inhibitors: rationale, mechanismsof action, and implications for drug resistance”, Semin Oncol 28(suppl16) 47-55 (2001); and Fabbro et al., “Protein tyrosine kinaseinhibitors: new treatment modalities?”, Current Opinion in Pharmacology,2:374-381 (2002).

The foregoing compounds may be synthesized using routine chemicaltechnologies and methods including those disclosed in U.S. patentapplication Ser. No. 10/256,879 (U.S. Pub. No. 20030199478) and Ser. No.10/259,703 (U.S. Pub. No. 20030225152) and the other above-identifiedreferences.

The present implants may also include salts of the TKIs.Pharmaceutically acceptable acid addition salts of the compounds of theinvention are those formed from acids which form non-toxic additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

Thus, the implant may comprise a therapeutic component which comprises,consists essentially of, or consists of a TKI, salts thereof, andmixtures thereof. The biodegradable polymer matrix of such implants maybe substantially free of polyvinyl alcohol, or in other words, includesno polyvinyl alcohol.

Additional TKIs may be obtained or synthesized using conventionalmethods, such as by routine chemical synthesis methods known to personsof ordinary skill in the art. Therapeutically effective TKIs may bescreened and identified using conventional screening technologies usedfor the TKIs described herein.

The TKIs may be in a particulate or powder form and entrapped by thebiodegradable polymer matrix. Usually, TKI particles in intraocularimplants will have an effective average size less than about 3000nanometers. In certain implants, the particles may have an effectiveaverage particle size about an order of magnitude smaller than 3000nanometers. For example, the particles may have an effective averageparticle size of less than about 500 nanometers. In additional implants,the particles may have an effective average particle size of less thanabout 400 nanometers, and in still further embodiments, a size less thanabout 200 nanometers.

The TKI of the implant is preferably from about 10% to 90% by weight ofthe implant. More preferably, the TKI is from about 20% to about 80% byweight of the implant. In a preferred embodiment, the TKI comprisesabout 40% by weight of the implant (e.g., 30%-50%). In anotherembodiment, the TKI comprises about 60% by weight of the implant.

Suitable polymeric materials or compositions for use in the implantinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably are atleast partially and more preferably substantially completelybiodegradable or bioerodible.

Examples of useful polymeric materials include, without limitation, suchmaterials derived from and/or including organic esters and organicethers, which when degraded result in physiologically acceptabledegradation products, including the monomers. Also, polymeric materialsderived from and/or including, anhydrides, amides, orthoesters and thelike, by themselves or in combination with other monomers, may also finduse. The polymeric materials may be addition or condensation polymers,advantageously condensation polymers. The polymeric materials may becross-linked or non-cross-linked, for example not more than lightlycross-linked, such as less than about 5%, or less than about 1% of thepolymeric material being cross-linked. For the most part, besides carbonand hydrogen, the polymers will include at least one of oxygen andnitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g.hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylicacid ester, and the like. The nitrogen may be present as amide, cyanoand amino. The polymers set forth in Heller, Biodegradable Polymers inControlled Drug Delivery, In: CRC Critical Reviews in Therapeutic DrugCarrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90,which describes encapsulation for controlled drug delivery, may find usein the present implants.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyesters,polyethers and combinations thereof which are biocompatible and may bebiodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Equally important to controlling the biodegradation of the polymer andhence the extended release profile of the implant is the relativeaverage molecular weight of the polymeric composition employed in theimplant. Different molecular weights of the same or different polymericcompositions may be included in the implant to modulate the releaseprofile. In certain implants, the relative average molecular weight ofthe polymer will range from about 9 to about 64 kD, usually from about10 to about 54 kD, and more usually from about 12 to about 45 kD.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation is controlled by the ratio of glycolicacid to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic acid and lactic acid. Homopolymers, orcopolymers having ratios other than equal, are more resistant todegradation. The ratio of glycolic acid to lactic acid will also affectthe brittleness of the implant, where a more flexible implant isdesirable for larger geometries. The % of polylactic acid in thepolylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some implants,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the intraocular implant may comprisea mixture of two or more biodegradable polymers. For example, theimplant may comprise a mixture of a first biodegradable polymer and adifferent second biodegradable polymer. One or more of the biodegradablepolymers may have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or a combination of both. As discussed herein, thematrix of the intraocular implant may release drug at a rate effectiveto sustain release of an amount of the TKI for more than one week afterimplantation into an eye. In certain implants, therapeutic amounts ofthe TKI are released for more than about one month, and even for aboutsix months or more.

One example of the biodegradable intraocular implant comprises a TKIwith a biodegradable polymer matrix that comprises apoly(lactide-co-glycolide) or a poly (D,L-lactide-co-glycolide). Theimplant may have an amount of the TKI from about 20% to about 60% byweight of the implant. Such a mixture is effective in sustaining releaseof a therapeutically effective amount of the TKI for a time period fromabout one month to about six months from the time the implant is placedin an eye.

Another example of the biodegradable intraocular implant comprises a TKIwith a biodegradable polymer matrix that comprises a single type ofpolymer. For example, the biodegradable polymer matrix may consistessentially of a polycaprolactone. The polycaprolactone may have amolecular weight between about 10 and about 20 kilodaltons, such asabout 15 kilodaltons. These implants are capable of providing a nearlylinear release rate for at least about 70 days.

The release of the TKI(s) from the intraocular implant comprising abiodegradable polymer matrix may include an initial burst of releasefollowed by a gradual increase in the amount of the TKI released, or therelease may include an initial delay in release of the TKI followed byan increase in release. When the implant is substantially completelydegraded, the percent of the TKI(s) that has been released is about onehundred. Compared to existing implants, the implants disclosed herein donot completely release, or release about 100% of the TKI(s), until afterabout one week of being placed in an eye.

It may be desirable to provide a relatively constant rate of release ofthe TKI(s) from the implant over the life of the implant. For example,it may be desirable for the TKI(s) to be released in amounts from about0.01 μg to about 2 μg per day for the life of the implant. However, therelease rate may change to either increase or decrease depending on theformulation of the biodegradable polymer matrix. In addition, therelease profile of the TKI(s) may include one or more linear portionsand/or one or more non-linear portions. Preferably, the release rate isgreater than zero once the implant has begun to degrade or erode.

The implants may be monolithic, i.e. having the active agent or agentshomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. Due to ease of manufacture, monolithic implants are usuallypreferred over encapsulated forms. However, the greater control affordedby the encapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. In addition, the therapeutic component, including theTKI(s), may be distributed in a non-homogenous pattern in the matrix.For example, the implant may include a portion that has a greaterconcentration of the TKI(s) relative to a second portion of the implant.

The implant may comprise a first portion comprising a mixture of thetyrosine kinase inhibitor and a biodegradable polymer, and a differentsecond portion comprising a biodegradable polymer substantially free ofthe tyrosine kinase inhibitor.

One such implant 100 is illustrated in FIG. 14. The implant 100 may beunderstood to be a unidirectional drug delivery device. The implant 100is characterized by comprising a first portion 110 and a second portion120. First portion 110 comprises a mixture of a therapeutic agent, suchas TKI, and a biodegradable polymer matrix, such as a matrix of PLGA,PLA, or a combination thereof. Second portion 120 comprises a polymer,such as a biodegradable polymer, and is substantially free of thetherapeutic agent. The polymeric component of the first portion 110 andthe second portion 120 may comprise the same polymer material, e.g.,both components may be made from a PLGA polymer. Although thetherapeutic agent is a TKI, other implants may include other therapeuticagents, including those described herein. First portion 110 may beunderstood to be an active layer, and second portion 120 may beunderstood to be a barrier layer, which is effective to prevent orreduce diffusion of the therapeutic agent from one side of the implant.The layers may be separately formed as films and pressed together usinga Carver press, for example. Or the layers may be co-extruded usingconventional extrusion techniques or injection molded using injectionmolding techniques. The implant 110 is effective to control the flow orrelease of a therapeutic agent in a specific direction, such as onedirection. The implant can be applied to a diseased location, such as inan eye, that needs the release of the therapeutic agent in a specificand controlled manner, such as for subconjunctival applications.

The present implants may also comprise a combination of a TKI andpolycaprolactone, as described herein. Such implants may provide asingle order release rate for about 70 days or more after placement inan eye. The polycaprolactone may have a molecular weight of about 15kilodaltons. Thus, one embodiment of the present implants, comprises apoorly soluble drug or therapeutic agent and a single polymericcomponent that releases the drug at a substantially linear release rate(e.g., a zero order rate).

The implant may comprise a matrix comprising a single type of polymer,wherein the implant releases the tyrosine kinase inhibitor for about 70days at a substantially linear rate.

The present implants may also include a non-biodegradable polymercomponent, as described herein. The release of a therapeutic agent, suchas TKI, may be achieved by movement of the therapeutic agent through oneor more openings, orifices, or holes. An example of such an implant isdisclosed in U.S. Pat. No. 6,331,313.

The intraocular implants disclosed herein may have a size of betweenabout 5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. For non-humanindividuals, the dimensions and total weight of the implant(s) may belarger or smaller, depending on the type of individual. For example,humans have a vitreous volume of approximately 3.8 ml, compared withapproximately 30 ml for horses, and approximately 60-100 ml forelephants. An implant sized for use in a human may be scaled up or downaccordingly for other animals, for example, about 8 times larger for animplant for a horse, or about, for example, 26 times larger for animplant for an elephant.

Thus, implants can be prepared where the center may be of one materialand the surface may have one or more layers of the same or a differentcomposition, where the layers may be cross-linked, or of a differentmolecular weight, different density or porosity, or the like. Forexample, where it is desirable to quickly release an initial bolus ofdrug, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The implants may be of any geometry including fibers, sheets, films,microspheres, spheres, circular discs, plaques and the like. The upperlimit for the implant size will be determined by factors such astoleration for the implant, size limitations on insertion, ease ofhandling, etc. Where sheets or films are employed, the sheets or filmswill be in the range of at least about 0.5 mm×0.5 mm, usually about 3-10mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling.Where fibers are employed, the fiber diameter will generally be in therange of about 0.05 to 3 mm and the fiber length will generally be inthe range of about 0.5-10 mm. Spheres may be in the range of about 0.5μm to 4 mm in diameter, with comparable volumes for other shapedparticles.

The size and form of the implant can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of the implant are chosento suit the site of implantation.

The proportions of TKI(s), polymer, and any other modifiers may beempirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the implant is added to a measured volume of a solutioncontaining 0.9% NaCl in water, where the solution volume will be suchthat the drug concentration is after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly tomaintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

In addition to the TKI(s) included in the intraocular implants disclosedherein, the intraocular implants may also include one or more additionalophthalmically acceptable therapeutic agents. For example, the implantmay include one or more antihistamines, one or more antibiotics, one ormore beta blockers, one or more steroids, one or more antineoplasticagents, one or more immunosuppressive agents, one or more antiviralagents, one or more antioxidant agents, and mixtures thereof.

Pharmacologic or therapeutic agents which may find use in the presentsystems, include, without limitation, those disclosed in U.S. Pat. No.4,474,451, columns 4-6 and U.S. Pat. No. 4,327,725, columns 7-8.

Examples of antihistamines include, and are not limited to, loradatine,hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazinedoxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, andderivatives thereof.

Examples of antibiotics include without limitation, cefazolin,cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan,cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin,cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,cefadroxil, cephradine, cefuroxime, cyclosporine, ampicillin,amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin Vpotassium, piperacillin, oxacillin, bacampicillin, cloxacillin,ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin,erythromycin, tetracycline, doxycycline, minocycline, aztreonam,chloramphenicol, ciprofloxacin hydrochloride, clindamycin,metronidazole, gentamicin, lincomycin, tobramycin, vancomycin, polymyxinB sulfate, colistimethate, colistin, azithromycin, augmentin,sulfamethoxazole, trimethoprim, gatifloxacin, ofloxacin, and derivativesthereof.

Examples of beta blockers include acebutolol, atenolol, labetalol,metoprolol, propranolol, timolol, and derivatives thereof.

Examples of steroids include corticosteroids, such as cortisone,prednisolone, flurometholone, dexamethasone, medrysone, loteprednol,fluazacort, hydrocortisone, prednisone, betamethasone, prednisone,methylprednisolone, riamcinolone hexacatonide, paramethasone acetate,diflorasone, fluocinonide, fluocinolone, triamcinolone, derivativesthereof, and mixtures thereof.

Examples of antineoplastic agents include adriamycin, cyclophosphamide,actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin,mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU),methyl-CCNU, cisplatin, etoposide, interferons, camptothecin andderivatives thereof, phenesterine, taxol and derivatives thereof,taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen,etoposide, piposulfan, cyclophosphamide, and flutamide, and derivativesthereof.

Examples of immunosuppresive agents include cyclosporine, azathioprine,tacrolimus, and derivatives thereof.

Examples of antiviral agents include interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, valciclovir,dideoxycytidine, phosphonoformic acid, ganciclovir and derivativesthereof.

Examples of antioxidant agents include ascorbate, alpha-tocopherol,mannitol, reduced glutathione, various carotenoids, cysteine, uric acid,taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin,cryotpxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine,gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid,citrate, Ginkgo Biloba extract, tea catechins, bilberry extract,vitamins E or esters of vitamin E, retinyl palmitate, and derivativesthereof.

Other therapeutic agents include squalamine, carbonic anhydraseinhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics,antifungals, and derivatives thereof.

The amount of active agent or agents employed in the implant,individually or in combination, will vary widely depending on theeffective dosage required and the desired rate of release from theimplant. As indicated herein, the agent will be at least about 1, moreusually at least about 10 weight percent of the implant, and usually notmore than about 80, more usually not more than about 40 weight percentof the implant.

In addition to the therapeutic component, the intraocular implantsdisclosed herein may include effective amounts of buffering agents,preservatives and the like. Suitable water soluble buffering agentsinclude, without limitation, alkali and alkaline earth carbonates,phosphates, bicarbonates, citrates, borates, acetates, succinates andthe like, such as sodium phosphate, citrate, borate, acetate,bicarbonate, carbonate and the like. These agents advantageously presentin amounts sufficient to maintain a pH of the system of between about 2to about 9 and more preferably about 4 to about 8. As such the bufferingagent may be as much as about 5% by weight of the total implant.Suitable water soluble preservatives include sodium bisulfite, sodiumbisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricborate, phenylmercuric nitrate, parabens, methylparaben, polyvinylalcohol, benzyl alcohol, phenylethanol and the like and mixturesthereof. These agents may be present in amounts of from 0.001 to about5% by weight and preferably 0.01 to about 2% by weight.

In addition, the implants may include a solubility enhancing componentprovided in an amount effective to enhance the solubility of the TKI(s)relative to substantially identical implants without the solubilityenhancing component. For example, an implant may include aβ-cyclodextrin, which is effective in enhancing the solubility of theTKI. The β-cyclodextrin may be provided in an amount from about 0.5%(w/w) to about 25% (w/w) of the implant. In certain implants, theβ-cyclodextrin is provided in an amount from about 5% (w/w) to about 15%(w/w) of the implant

In some situations mixtures of implants may be utilized employing thesame or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried. The implants may also have a sigmoidal release profile.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of the TKI in theabsence of modulator. Electrolytes such as sodium chloride and potassiumchloride may also be included in the implant. Where the buffering agentor enhancer is hydrophilic, it may also act as a release accelerator.Hydrophilic additives act to increase the release rates through fasterdissolution of the material surrounding the drug particles, whichincreases the surface area of the drug exposed, thereby increasing therate of drug bioerosion. Similarly, a hydrophobic buffering agent orenhancer dissolve more slowly, slowing the exposure of drug particles,and thereby slowing the rate of drug bioerosion.

Various techniques may be employed to produce the implants describedherein. Useful techniques include, but are not necessarily limited to,solvent evaporation methods, phase separation methods, interfacialmethods, molding methods, injection molding methods, extrusion methods,co-extrusion methods, carver press method, die cutting methods, heatcompression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the implants, and typicallyyield implants with faster release rates than extrusion methods.Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

The implants of the present invention may be inserted into the eye, forexample the vitreous chamber of the eye, by a variety of methods,including placement by forceps or by trocar following making a 2-3 mmincision in the sclera. One example of a device that may be used toinsert the implants into an eye is disclosed in U.S. Patent PublicationNo. 2004/0054374. The method of placement may influence the therapeuticcomponent or drug release kinetics. For example, delivering the implantwith a trocar may result in placement of the implant deeper within thevitreous than placement by forceps, which may result in the implantbeing closer to the edge of the vitreous. The location of the implantmay influence the concentration gradients of therapeutic component ordrug surrounding the element, and thus influence the release rates(e.g., an element placed closer to the edge of the vitreous may resultin a slower release rate).

The present implants are configured to release an amount of the TKI(s)effective to treat or reduce a symptom of an ocular condition.

The implants disclosed herein may also be configured to release the TKIor additional therapeutic agents, as described above, which to preventdiseases or conditions, such as the following:

MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, Cystoid MacularEdema, Diabetic Macular Edema.

UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid PigmentEpitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy,Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), IntermediateUveitis (Pars Planitis), Multifocal Choroiditis, Multiple EvanescentWhite Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis,Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome,Vogt-Koyanagi-Harada Syndrome.

VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease, ParafovealTelangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle CellRetinopathy and other Hemoglobinopathies, Angioid Streaks, FamilialExudative Vitreoretinopathy.

TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease,Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, HypoperfusionDuring Surgery, Radiation Retinopathy, Bone Marrow TransplantRetinopathy.

PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy andEpiretinal Membranes, Proliferative Diabetic Retinopathy, Retinopathy ofPrematurity (retrolental fibroplastic).

INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associated with HIV Infection, Uveitic Disease Associated withHIV Infection, Viral Retinitis, Acute Retinal Necrosis, ProgressiveOuter Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.

GENETIC DISORDERS: Systemic Disorders with Accosiated RetinalDystrophies, Congenital Stationary Night Blindness, Cone Dystrophies,Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the RetinalPigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy,Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy,pseudoxanthoma elasticum, Osler Weber syndrome.

RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant RetinalTear.

TUMORS: Retinal Disease Associated with Tumors, Solid Tumors, TumorMetastasis, Benign Tumors, for example, hemangiomas, neurofibromas,trachomas, and pyogenic granulomas, Congenital Hypertrophy of the RPE,Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma,Choroidal Metastasis, Combined Hamartoma of the Retina and RetinalPigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of theOcular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior MultifocalPlacoid Pigment Epitheliopathy, Myopic Retinal Degeneration, AcuteRetinal Pigment Epithelitis, Ocular inflammatory and immune disorders,ocular vascular malfunctions, Corneal Graft Rejection, NeovascularGlaucoma and the like.

In one embodiment, an implant, such as the implants disclosed herein, isadministered to a posterior segment of an eye of a human or animalpatient, and preferably, a living human or animal. In at least oneembodiment, an implant is administered without accessing the subretinalspace of the eye. For example, a method of treating a patient mayinclude placing the implant directly into the posterior chamber of theeye. In other embodiments, a method of treating a patient may compriseadministering an implant to the patient by at least one of intravitrealinjection, subconjuctival injection, sub-tenon injections, retrobulbarinjection, and suprachoroidal injection.

In at least one embodiment, a method of improving vision or maintainingvision in a patient comprises administering one or more implantscontaining one or more TKIs, as disclosed herein to a patient by atleast one of intravitreal injection, subconjuctival injection, sub-tenoninjection, retrobulbar injection, and suprachoroidal injection. Asyringe apparatus including an appropriately sized needle, for example,a 22 gauge needle, a 27 gauge needle or a 30 gauge needle, can beeffectively used to inject the composition with the posterior segment ofan eye of a human or animal. Repeat injections are often not necessarydue to the extended release of the TKI from the implants.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container comprisingan extended release implant comprising a therapeutic component includinga TKI, and a drug release sustaining component; and b) instructions foruse. Instructions may include steps of how to handle the implants, howto insert the implants into an ocular region, and what to expect fromusing the implants.

EXAMPLE 1 Intravitreal Pharmacokinetics of TKIs in Fluid Compositions

The ocular pharmacokinetics of AGN 199659, AGN 200954, AGN 201088 andAGN 201666 following single intravitreal injections into female albinorabbit eyes was determined. The animals were dosed with a 50 μLintravitreal injection of 242 ng AGN 201088, 128 ng AGN 201666, 114 ngAGN 199659 or 222 ng AGN 200954 per eye. vitreous humor samples (n=4eyes per timepoint) were collected at 0.5, 1, 2, 4, 8, and 12 hrpostdose. The TKI concentration in the vitreous humor was determinedusing a liquid chromatography tandem mass spectrometry method(LC-MS/MS).

All compounds were eliminated fairly rapidly from the rabbit eye. Thisindicates a transretinal route of elimination. There was no bias tocompound nucleus. However, even though elimination was extremely rapidit was determined that local sustained delivery was feasible. Based onthe vitreal clearance determined in this study for3-[(4-Morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-(6-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one,AGN 201088 and AGN 201666, and assuming steady state efficaciousconcentration at twice the EC50 values (determined by in vitro receptorbinding and intracellular Ca2+ assay) all the tyrosine kinase inhibitorstested could be formulated into 1 mg implants that would maintain thedesired steady state drug vitreal concentrations for a duration of aboutsix months. This data is summarized in Table 1 and FIGS. 1 and 2.

TABLE 1 TKI Pharmacokinetic Parameters after a Single IntravitrealInjection AGN AGN AGN AGN Parameter 199659 200954 201088 201666 Dose(ng) 114 222 242 128 C₀ ₍ng/mL) 502 566 222 332 t_(1/2) (hr) 1.21 2.591.11 2.32 AUC_(0-tlast) 488 778 272 466 (ng · hr/mL) Cl (mL/hr) 0.2320.260 0.885 0.270 V_(ss) (mL) 0.255 0.705 1.23 0.577 Theoretical 6 200ug 5 ug 150 ug 126 ug mo dose

EXAMPLE 2 TKI Biodegradable Implants

Tyrosine kinase inhibitors were incorporated into PLGA or PLA implantsby extrusion. The TKIs were milled with the polymers at certain ratiosthen extruded into filaments. These filaments were subsequently cut intoimplants weighing approximately 1 mg. Several TKIs were formulated inthe PLGA and PLA implants based on their potencies and physicochemicalproperties as shown in Table 2.

TABLE 2 Tyrosine Kinase Inhibitors Formulated in PLGA Implants AGNNumber Structure Projected C_(ss) Efficacy Solubility (μg/mL) pH 7 log PpKa AGN 200954

4 ng/mL 0.3 2.21 4.24 10.03 AGN 202314

96 ng/mL 202 3.80 9.68 AGN 202560

105 ng/mL 41 3.66 9.65 AGN 201634

28 ng/mL 88 1.25 4.06 10.25

TKI release from the implants was assessed in vitro. Implants wereplaced into vials containing release medium and shaken at 37° C. At theappropriate time points a sample was taken from the release medium foranalysis and the medium totally replaced to maintain sink conditions.Drug in the sample was assayed by HPLC and the cumulative percentrelease of drug from the implant noted as a function of time. The invitro release profiles of AGN 200954, AGN 202314, AGN 201635 and AGN202564 are depicted in FIGS. 3 through 10, respectively.

From the formulation release data depicted in FIGS. 3 through 10 it isevident that TKIs over a wide range of physicochemical properties can beengineered to release drug in vitro over a period of weeks to a year.

EXAMPLE 3 In Vivo Pharmacokinetic Properties of TKI-Containing Implants

Implants containing AGN 202314 were placed intravitreally orsubconjunctivally in an eye. The implants released AGN 202314 in-vitroover a 14 day period (FIG. 3.). The intent of this study was to achievean intravitreal in-vivo/in-vitro correlation with the intravitrealimplants and assess the feasibility of periocular delivery.

Intravitreal Implants, PLGA (400 μg AGN 202314 dose, 1 mg total implantweight), were implanted by surgical incision into the mid vitreous ofalbino rabbits. At days 8, 15, 31 and 61 rabbits were sacrificed and thevitreous humor, lens, aqueous humor and plasma assayed for AGN 202314.

Subconjunctival implants, PLGA (1200 μg AGN 202314 dose; three implants)and PLA microspheres (300 μg AGN 202314) were implantedsubconjunctivally. At days 8, 15, 31 and 61 rabbits were sacrificed andthe vitreous humor, lens, aqueous humor and plasma assayed for AGN202314.

The data are summarized in Tables 3 through 5

TABLE 3 PK Results from 2 Month Intravitreal Implantation AGN 202314Implant (400 μg rod) Day 8 15 31 61 Retina (ng/g) 1220 100 BLQ BLQVitreous 327 85 BLQ BLQ Humor (ng/g) Lens (ng/g) ALQ (6580) ALQ (8980)724 35.8 Aqueous 2.10 6.50 BLQ BLQ Humor (ng/mL) Plasma 0.255 BLQ BLQBLQ (ng/mL) Below the limit of quantitation (BLQ): Retina and lens: <5ng/g, VH: <30 ng/g, AH: <0.5 ng/mL, Plasma: <0.5 ng/mL Above the limitof quantitation (ALQ): Retina and lens: >2000 ng/g, VH: >3000 ng/g,AH: >30 ng/mL, Plasma: >200 ng/mL

TABLE 4 PK Results from 2 Mo Suboncjunctival Implantation of AGN 202314Microspheres Day 8 15 31 61 Microsphere (300 μg AGN 202314) - 0.63 dL/gPLA Retina (ng/g) 12.4 BLQ 19.2 BLQ Vitreous BLQ BLQ BLQ BLQ Humor(ng/g) Lens (ng/g) 5.19 BLQ BLQ BLQ Aqueous BLQ BLQ BLQ BLQ Humor(ng/mL) Plasma BLQ BLQ BLQ BLQ (ng/mL) Microsphere (300 μg AGN 202314) -1.2 dL/g PLA Retina (ng/g) 3.7 5.1 BLQ BLQ Vitreous BLQ BLQ BLQ BLQHumor (ng/g) Lens (ng/g) BLQ BLQ 2.72 BLQ Aqueous BLQ BLQ BLQ BLQ Humor(ng/mL) Plasma BLQ BLQ BLQ BLQ (ng/mL) BLQ = Retina (<5 ng/g), VH (<30ng/g), lens (<5 ng/g), AH (<0.5 ng/mL), plasma (<0.5 ng/mL)

TABLE 5 Month Subconjunctival Implantation (3 rods with a total of 1.2mg AGN 202314) Day 8 15 31 61 Retina (ng/g) 63.8 BLQ BLQ BLQ VitreousBLQ BLQ BLQ BLQ Humor (ng/g) Lens (ng/g) 229 7.93 BLQ BLQ Aqueous 6.38BLQ BLQ BLQ Humor (ng/mL) Plasma BLQ BLQ BLQ BLQ (ng/mL) BLQ: Retina andlens: <5 ng/g, VH: <30 ng/g, AH: <0.5 ng/mL, Plasma: <0.5 ng/mL

The data from this study indicates that a good in vitro in vivocorrelation was established for AGN 202314. The AGN 202314 implantreleased drug over a two week period both in vitro and in vivo. It isalso important that plasma levels remain BLQ or extremely low for alltime points. This shows that even in a worst case scenario ofintravitreal delivery over two weeks systemic exposure is negligible. Itwas also noted that periocular delivery was unsuccessful at deliveringAGN 202314 to the vitreous and retina.

A follow-on two-month ocular pharmacokinetic study of AGN 202314following a single intravitreal implantation into albino rabbit eyes wasinitiated. The formulations delivered AGN 202314 over a period of fourmonths in-vitro. The following 1 mg implants were evaluated: 30% AGN202314/70% Purac PLA; Lot# JS493028 (FIG. 4), 50% AGN 201634/50% PuracPLA; Lot # JS493034 (FIG. 6.).

Two rabbits (4 eyes and 2 plasma) were used per timepoint. Implants wereadministered by a bilateral surgical intravitreal placement bysclerotomy without vitrectomy. The vitreous humor and retina AGN 202314concentrations were assayed at days 8, 15, 31 and 61. The data aredisplayed in Table 6.

TABLE 6 One Month Data from the AGN 202314 Intravitreal Study Day 8 1531 50% Purac PLA (AGN 202314 - 500 μg) Retina (ng/g) 95.3 ± 18.7 87.7 ±29.6 157 ± 120 VH (ng/g): 22.2 ± 25.6 BLQ 69.9 ± 87.5 70% Purac PLA (AGN202314 - 300 μg) Retina (ng/g) 78.1 ± 7.2   197 ± 88.7 189 ± 126 VH(ng/g) BLQ 33.7 ± 25.8 BLQ Analytical range: Retina BLQ < 5 ng/g; VH BLQ< 30 ng/g

The retinal levels achieved from this study approach therapeutic levelsby the first week and are maintained over the first thirty days. Thisdata shows that actual in vivo sustained delivery of a TKI locally isfeasible.

A six month pharmacokinetic study was initiated with intravitreal andsubconjunctival AGN 200954 implants. The implants released AGN 200954in-vitro over a 180 day period (FIG. 3). Intravitreal Implants, PLGA(500 μg AGN 200954 dose, 1 mg total implant weight, Purac polymer) andPLGA (500 μg AGN 200954 dose, 1 mg total implant weight, RG503Hpolymer), were implanted by surgical incision into the mid vitreous ofalbino rabbits. At days 8, 15, 31 and 61 rabbits were sacrificed and thevitreous humor, lens, aqueous humor and plasma assayed for AGN 200954.Subconjunctival implants, PLGA implant (500 μg AGN 200954 dose, 1 mgtotal implant weight, Purac polymer) and PLGA microspheres (370 μg and740 μg AGN 200954), were administered. At days 8, 15, 31 and 61 rabbitswere sacrificed and the vitreous humor, lens, aqueous humor and plasmaassayed for AGN 200954.

AGN 200954 Pharmacokinetics after Intravitreal Administration

Day 8 31 61 91 181 Intravitreal Implantation (500 μg rod) Formulation PURetina BLQ 48.7 207 161 210 (ng/g) Vitreous BLQ 18.2 109 657 76.3 Humor(ng/g) Lens (ng/g) 70.2 243 586 768 1296 Aqueous BLQ BLQ BLQ BLQ 288Humor (ng/mL) Plasma BLQ BLQ BLQ BLQ BLQ (ng/mL) IntravitrealImplantation (500 μg rod) Formulation RG503H Retina 15.7 17.7 416 58.424.9 (ng/g) Vitreous 560 126 189 65.2 227 Humor(ng/g) Lens (ng/g) 160386 464 239 248 Aqueous BLQ BLQ BLQ BLQ 316 Humor (ng/mL) Plasma BLQ BLQBLQ BLQ BLQ (ng/mL) BLQ = Retina (5 ng/g), VH (30 ng/g), lens (5 ng/g),AH (0.05 ng/mL), plasma (0.05 ng/mL)

It is evident from the data that a considerable in-vivo lag time existsfor the first formulation not seen in vitro. Neither formulationexhibits measurable plasma concentrations.

EXAMPLE 4 In Vitro Release of a TKI (AGN 201634) from an Implant

TKI release was examined for implants made frompoly(D,L-lactide-co-glycolide) (PDLG) or poly(D,L-lactide)(PDL) indifferent media with or without addition of detergent at 37° C. in ashaking water bath.

AGN 201634 was obtained from Allergan, and its chemical structure isshown below. It was used as received without further purification.PDLG/PDL polymer materials were obtained from Purac America Inc.

TKI release was examined in various medium, including saline, phosphatebuffer saline of pH 7.4, 50 mM bicarbonate buffer of pH 6.0±0.1 with0.1% cetyltrimethylammonium bromide (CTAB), and 50 mM borate buffer ofpH 8.5±0.1 with 0.5% sodium dodecyl sulfate (SDS) in a shaking waterbath (Precision) at 37° C. Sample was incubated in 10 mL of medium, andwas totally replaced with fresh medium at each sampling time. Drugconcentration was determined by HPLC using a Waters 2690 SeparationModule equipped with a Waters XTerra RP8 column (3.9×150 mm, 5 μm,equilibrated at ambient) and a Waters 996 photodiode array detector (setat 238 nm) using 0.1% acetic acid in acetonitrile/water (40/60 byvolume) as the mobile phase under a flow rate of 1.2 mL/min. The columnwas equilibrated with mobile phase for at least 30 min before initiatingany sample injection.

The characteristics of formulations, including formulationidentification, Lot number, drug loading, inherent viscosity of polymer,and extrusion temperature are summarized in the following table. Thedrug load is from 20 to 50%. The formulations were extruded from a 750μm nozzle to form cylindrical DDS.

TABLE 8 Characteristics of TKI formulations. Drug Formulation LoadingExtrusion Temp # Lot # (%) Polymer I.V. (° C.) F1 JS443159 40 PDLG 0.268 F2 JS443020 20 PDLG 0.2 70 F3 JS493023 50 PDL 0.5 85 F4 JS493034 30PDL 0.5 78 Note: I.V.: inherent viscosity of polymer material.

The stability of AGN 201634 standard solution in deionizedwater/acetonitrile (75%/25%) was examined at 4° C., and the results aresummarized in the following table. The concentration of standardsolution was from 0.0695 μg/mL to 8.693 μg/mL, and was analyzed on day14, 21, and 35. The results show that the recovery was all greater than95%, indicating a good stability of AGN 201634 in deionizedwater/acetonitrile (75%/25%) at 4° C. for up to 35 days even theconcentration was up to 8.7 μg/mL.

Stability of AGN 201634 Standard Solution of Various Concentrations inDI Water/Acetonitrile (75%/25%) at 4° C. (Table 9).

Conc. Of Standard Day (μg/mL) Recovery (%) 14 0.0695 95.2 0.348 98.30.695 98.4 2.173 98.6 8.693 98.6 21 0.0695 96.5 0.348 101.3 0.695 102.12.173 101.0 8.693 101.6 35 0.0695 106.1 0.348 98.3 0.695 101.3 2.173100.8 8.693 100.3

To examine the stability of TKI in formulation, Formulations 3 and 4were prepared to various concentration in a medium of pH 6.0, 7.4 or8.5, respectively, and subjected to an incubation condition of either 7days under ambient condition or 14 days at 4° C., and the results aresummarized in the following table. The results show that the recoverywas all better than 98%, indicating that AGN 201634 was stable in mediaof pH 6.0, 7.4 and 8.5, and lasted for 7 days in ambient or 14 days at4° C.

TABLE 10 Stability of TKI in Formulations 3 and 4 in media under variousincubation conditions. Concen- Incubation tration Incubation TemperatureRecovery Formulation Medium (μg/mL) Time (day) (oC.) (%) F3 pH 6.0 5.607 ambient 100.1 3.45 14 4 102.7 pH 7.4 2.53 7 ambient 101.1 2.29 14 4103.7 pH 8.5 10.34 7 ambient 100.8 10.24 14 4 98.8 F4 pH 6.0 0.94 7ambient 100.4 0.84 14 4 102.4 pH 7.4 0.18 7 ambient 104.3 0.48 14 4101.3 pH 8.5 1.39 7 ambient 100.4 1.20 14 4 100.2

TKI releases of Formulation 1 in 20 mL of saline or 20-30 mL of PBS aredemonstrated in FIG. 11. The DDS was incubated in a vial of either 40 or20 mL, and 10 mL sample solution was replaced by same volume of freshmedium, respectively, at each sampling time. The release profiles insaline and PBS were obviously different. Less than 5% of TKI wasreleased in saline during the first 70 days. In contrast, less than 5%of AGN 201634 was released at the first 3 weeks when DDS was incubatedin PBS, the same as in saline, but more than 80% of AGN 201634 wasreleased after 70 days. However, no significantly difference in releaseprofile was found when DDS was incubated in 20 or 30 mL of PBS in a 20or 40 mL vial. It seems that release medium plans an important role inthe variation of release profile instead of incubation volume. Due tothis slow and diverged release profile, the release profile ofFormulation 2 was not performed since its formulation was based on thesame polymer with a lower drug loading.

TKI releases of Formulations 3 and 4 in 10 mL media of a pH of 6.0 (with0.1% CTAB), 7.4 (PBS) or 8.5 (with 0.5% SDS) at 37° C. are demonstratedin FIGS. 12 and 13, respectively. For F3, more than 50%, 45%, and 75%TKI was released at the first 3, 7, and 2 weeks, when DDS was incubatedin a medium of pH 6.0 (with 0.1% CTAB), 7.4 (PBS) and 8.5 (with 0.5%SDS), respectively. On the other hand, approximately 47%, 6%, and 68% ofTKI was released from F4 when DDS was incubated in media as describedabove. It seems that TKI release in different pH medium is pH 8.5>pH6.0>pH 7.4, with or without the assistant from detergent in the medium.No large standard deviations are found in all media for bothformulations.

To monitor the appearance of DDS during dissolution, the images of F3and F4 formulations incubated in 10 mL media of a pH of 6.0 (with 0.1%CTAB), 7.4 (PBS) or 8.5 (with 0.5% SDS) at 37° C. were. All formulationsexperienced swelling followed by matrix degradation, resulting in drugrelease. No complete disintegration of formulation matrix was observedwithin 153 days at 37° C.

In summary, tyrosine kinase inhibitor (AGN 201634) DDS were formulatedusing various PLGA or PLA at various drug loading. The stability of AGN201634 solution in DI water/acetonitrile (75%/25%) at 4° C. was morethan 35 days, and DDS solution in various pH medium was more than 7 daysunder ambient condition or 14 days at 4° C. Different drug releaseprofiles were found when DDS was tested in PBS or saline. Drug bursteffect was found only in Formulation 3 when incubating in a medium of pH6.0. Controlled AGN 201634 release in vitro was more than 4 weeks in amedium of pH 8.5, and more than 5 months in media of pH 7.4 and pH 6.0.

EXAMPLE 5 Biodegradable Implants with a Linear Release Profile

Biodegradable implants are made by combining a TKI with a biodegradablepolymer composition in a stainless steel mortar. The biodegradablepolymer composition comprises a single type of biodegradable polymer.The combination is mixed via a Turbula shaker set at 96 RPM for 15minutes. The powder blend is scraped off the wall of the mortar and thenremixed for an additional 15 minutes. The mixed powder blend is heatedto a semi-molten state at specified temperature for a total of 30minutes, forming a polymer/drug melt.

Rods are manufactured by pelletizing the polymer/drug melt using a 9gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into thebarrel and extruding the material at the specified core extrusiontemperature into filaments. The filaments are then cut into about 1 mgsize implants or drug delivery systems. The rods have dimensions ofabout 2 mm long×0.72 mm diameter. The rod implants weigh between about900 μg and 1100 μg.

Wafers are formed by flattening the polymer melt with a Carver press ata specified temperature and cutting the flattened material into wafers,each weighing about 1 mg. The wafers have a diameter of about 2.5 mm anda thickness of about 0.13 mm. The wafer implants weigh between about 900μg and 1100 μg.

In-vitro release testing can be performed on each lot of implant (rod orwafer). Each implant may be placed into a 24 mL screw cap vial with 10mL of Phosphate Buffered Saline solution at 37° C. and 1 mL aliquots areremoved and replaced with equal volume of fresh medium on day 1, 4, 7,14, 28, and every two weeks thereafter.

Drug assays may be performed by HPLC, which consists of a Waters 2690Separation Module (or 2696), and a Waters 2996 Photodiode ArrayDetector. An Ultrasphere, C-18 (2), 5 μm; 4.6×150 mm column heated at30° C. can be used for separation and the detector can be set at 264 nm.The mobile phase can be (10:90) MeOH-buffered mobile phase with a flowrate of 1 mL/min and a total run time of 12 min per sample. The bufferedmobile phase may comprise (68:0.75:0.25:31) 13 mM 1-Heptane SulfonicAcid, sodium salt-glacial acetic acid-triethylamine-Methanol. Therelease rates can be determined by calculating the amount of drug beingreleased in a given volume of medium over time in μg/day.

The single polymer chosen for the implant was poly(caprolactone). Rodand wafer implants were formulated at a ratio of 50:50(poly(caprolactone):TKI). Thus, a 1 mg implant comprises about 500 μgpoly(caprolactone) and 500 μg TKI. AGN 200954 was used as the TKI.

As shown in FIG. 15, implants formed from a poorly soluble drug (TKI)and a single type of a biodegradable polymer (poly(caprolactone))released TKI at nearly zero-order rate for at least about 70 days. Theparticular poly(caprolactone) had a molecular weight of about 15kilodaltons. The nearly linear release rate is extremely hard to achievewith other biodegradable implants based on a single polymeric component,as shown for the dexamethasone containing implants in FIG. 15.

EXAMPLE 6 Manufacture and Testing of Implants Containing an TKI and aBiodegradable Polymer Matrix

Additional biodegradable implants are made by combining a TKI with abiodegradable polymer composition as described in Example 5. Thepolymers chosen for the implants can be obtained from BoehringerIngelheim or Purac America, for example. Examples of polymers include:RG502, RG752, R202H, R203 and R206, and Purac PDLG (50/50). RG502 is(50:50) poly(D,L-lactide-co-glycolide), RG752 is (75:25)poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide) withacid end group or terminal acid groups, R203 and R206 are both 100%poly(D, L-lactide). Purac PDLG (50/50) is (50:50)poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752,R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2dL/g, respectively. The average molecular weight of RG502, RG752, R202H,R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and9700 daltons, respectively.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1. A biodegradable intraocular implant comprising: a tyrosine kinaseinhibitor and a biodegradable polymer matrix that releases drug at arate effective to sustain release of an amount of the tyrosine kinaseinhibitor from the implant for at least about one week after the implantis placed in an eye, wherein said tyrosine kinase inhibitor is acompound having the formula


2. The implant of claim 1, further comprising an additionalophthalmically acceptable therapeutic agent.
 3. The implant of claim 1,wherein the tyrosine kinase inhibitor is dispersed within thebiodegradable polymer matrix.
 4. The implant of claim 1, wherein thematrix comprises at least one polymer selected from the group consistingof polylactides, poly (lactide-co-glycolides), polycaprolactones,derivatives thereof, and mixtures thereof.
 5. The implant of claim 1,wherein the implant comprises a first portion comprising a mixture ofthe tyrosine kinase inhibitor and a biodegradable polymer, and adifferent second portion comprising a biodegradable polymersubstantially free of the tyrosine kinase inhibitor.
 6. The implant ofclaim 1, wherein the matrix comprises a single type of polymer, and theimplant releases the tyrosine kinase inhibitor for about 70 days at asubstantially linear rate.
 7. The implant of claim 1, wherein the matrixreleases drug at a rate effective to sustain release of an amount of thetyrosine kinase inhibitor from the implant for more than one month fromthe time the implant is placed in the vitreous of the eye.
 8. Theimplant of claim 1, wherein the implant is structured to be placed inthe vitreous of the eye.
 9. The implant of claim 1, wherein the tyrosinekinase inhibitor is provided in an amount from about 40% by weight toabout 70% by weight of the implant, and the biodegradable polymer matrixcomprises a poly (lactide-co-glycolide) in an amount from about 30% byweight to about 60% by weight of the implant.
 10. The implant of claim 1formed as a rod, a wafer, or a particle.
 11. The implant of claim 1which is formed by an extrusion process.
 12. A biodegradable intraocularimplant comprising a tyrosine kinase inhibitor and a biodegradablepolymer matrix that releases drug at a rate effective to sustain releaseof an amount of the tyrosine kinase inhibitor from the implant for atleast about one week after the implant is placed in an eye, wherein saidtyrosine kinase inhibitor is a compound having the formula

and the implant is formed by an extrusion process.
 13. A biodegradableintraocular implant comprising a tyrosine kinase inhibitor and abiodegradable polymer matrix that releases drug at a rate effective tosustain release of an amount of the tyrosine kinase inhibitor from theimplant for at least about one week after the implant is placed in aneye, wherein said tyrosine kinase inhibitor is a compound having theformula

and the implant is formed as rod, a wafer or a particle.
 14. Abiodegradable intraocular implant consisting essentially of: a tyrosinekinase inhibitor and a biodegradable polymer matrix that releases drugat a rate effective to sustain release of an amount of the tyrosinekinase inhibitor from the implant for at least about one week after theimplant is placed in an eye, wherein said tyrosine kinase inhibitor is acompound having the formula


15. A biodegradable intraocular implant consisting of: a tyrosine kinaseinhibitor and a biodegradable polymer matrix that releases drug at arate effective to sustain release of an amount of the tyrosine kinaseinhibitor from the implant for at least about one week after the implantis placed in an eye, wherein said tyrosine kinase inhibitor is acompound having the formula